Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease

Loss-of-function mutations in the progranulin gene (PGRN) were identified in frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusions (FTLD-U). We assessed whether PGRN also contributes to genetic risk for Alzheimer disease (AD) in an extended Belgian AD patient gro...

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Veröffentlicht in:Neurology 2008-08, Vol.71 (9), p.656-664
Hauptverfasser: BROUWERS, N, SLEEGERS, K, SCHYMKOWITZ, J, ROUSSEAU, F, MARTIN, J.-J, CRUTS, M, DE DEYN, P. P, VAN BROECKHOVEN, C, ENGELBORGHS, S, MAURER-STROH, S, GIJSELINCK, I, VAN DER ZEE, J, PICKUT, B. A, VAN DEN BROECK, M, MATTHEIJSSENS, M, PEETERS, K
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container_end_page 664
container_issue 9
container_start_page 656
container_title Neurology
container_volume 71
creator BROUWERS, N
SLEEGERS, K
SCHYMKOWITZ, J
ROUSSEAU, F
MARTIN, J.-J
CRUTS, M
DE DEYN, P. P
VAN BROECKHOVEN, C
ENGELBORGHS, S
MAURER-STROH, S
GIJSELINCK, I
VAN DER ZEE, J
PICKUT, B. A
VAN DEN BROECK, M
MATTHEIJSSENS, M
PEETERS, K
description Loss-of-function mutations in the progranulin gene (PGRN) were identified in frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusions (FTLD-U). We assessed whether PGRN also contributes to genetic risk for Alzheimer disease (AD) in an extended Belgian AD patient group (n = 779, onset age 74.7 +/- 8.7 years). A mutation analysis of the PGRN coding region was performed. The effect of missense mutations was assessed using in silico predictions and protein modeling. Risk effects of common genetic variants were estimated by logistic regression analysis and gene-based haplotype association analysis. We observed seven missense mutations in eight patients (1.3%). Convincing pathogenic evidence was obtained for two missense mutations, p.Cys139Arg and p.Pro451Leu, affecting PGRN protein folding and leading to loss of PGRN by degradation of the misfolded protein. In addition, we showed that PGRN haplotypes were associated with increased risk for AD. Our data support a role for PGRN in patients with clinically diagnosed Alzheimer disease (AD). Further, we hypothesize that at least some PGRN missense mutations might lead to loss of functional protein. Whether the underlying pathology in our cases proves to be AD, frontotemporal lobar degeneration, or a combination of the two must await further investigations.
doi_str_mv 10.1212/01.wnl.0000319688.89790.7a
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P ; VAN BROECKHOVEN, C ; ENGELBORGHS, S ; MAURER-STROH, S ; GIJSELINCK, I ; VAN DER ZEE, J ; PICKUT, B. A ; VAN DEN BROECK, M ; MATTHEIJSSENS, M ; PEETERS, K</creator><creatorcontrib>BROUWERS, N ; SLEEGERS, K ; SCHYMKOWITZ, J ; ROUSSEAU, F ; MARTIN, J.-J ; CRUTS, M ; DE DEYN, P. P ; VAN BROECKHOVEN, C ; ENGELBORGHS, S ; MAURER-STROH, S ; GIJSELINCK, I ; VAN DER ZEE, J ; PICKUT, B. A ; VAN DEN BROECK, M ; MATTHEIJSSENS, M ; PEETERS, K</creatorcontrib><description>Loss-of-function mutations in the progranulin gene (PGRN) were identified in frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusions (FTLD-U). We assessed whether PGRN also contributes to genetic risk for Alzheimer disease (AD) in an extended Belgian AD patient group (n = 779, onset age 74.7 +/- 8.7 years). A mutation analysis of the PGRN coding region was performed. The effect of missense mutations was assessed using in silico predictions and protein modeling. Risk effects of common genetic variants were estimated by logistic regression analysis and gene-based haplotype association analysis. We observed seven missense mutations in eight patients (1.3%). Convincing pathogenic evidence was obtained for two missense mutations, p.Cys139Arg and p.Pro451Leu, affecting PGRN protein folding and leading to loss of PGRN by degradation of the misfolded protein. In addition, we showed that PGRN haplotypes were associated with increased risk for AD. Our data support a role for PGRN in patients with clinically diagnosed Alzheimer disease (AD). Further, we hypothesize that at least some PGRN missense mutations might lead to loss of functional protein. 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A mutation analysis of the PGRN coding region was performed. The effect of missense mutations was assessed using in silico predictions and protein modeling. Risk effects of common genetic variants were estimated by logistic regression analysis and gene-based haplotype association analysis. We observed seven missense mutations in eight patients (1.3%). Convincing pathogenic evidence was obtained for two missense mutations, p.Cys139Arg and p.Pro451Leu, affecting PGRN protein folding and leading to loss of PGRN by degradation of the misfolded protein. In addition, we showed that PGRN haplotypes were associated with increased risk for AD. Our data support a role for PGRN in patients with clinically diagnosed Alzheimer disease (AD). Further, we hypothesize that at least some PGRN missense mutations might lead to loss of functional protein. 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A</au><au>VAN DEN BROECK, M</au><au>MATTHEIJSSENS, M</au><au>PEETERS, K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease</atitle><jtitle>Neurology</jtitle><addtitle>Neurology</addtitle><date>2008-08-26</date><risdate>2008</risdate><volume>71</volume><issue>9</issue><spage>656</spage><epage>664</epage><pages>656-664</pages><issn>0028-3878</issn><eissn>1526-632X</eissn><coden>NEURAI</coden><abstract>Loss-of-function mutations in the progranulin gene (PGRN) were identified in frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusions (FTLD-U). We assessed whether PGRN also contributes to genetic risk for Alzheimer disease (AD) in an extended Belgian AD patient group (n = 779, onset age 74.7 +/- 8.7 years). A mutation analysis of the PGRN coding region was performed. 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subjects Aged
Aged, 80 and over
Alzheimer Disease - genetics
Amino Acid Sequence - genetics
Biological and medical sciences
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
DNA Mutational Analysis
Female
Genetic Markers - genetics
Genetic Predisposition to Disease - genetics
Genetic Testing
Genetic Variation - genetics
Haplotypes - genetics
Humans
Intercellular Signaling Peptides and Proteins - genetics
Male
Medical sciences
Middle Aged
Mutation, Missense - genetics
Neurology
Protein Folding
title Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease
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